Role of a Responsive Sympathetic Nervous System in the Chronic Hypotensive Effects of Losartan in Normal Rats

We have previously demonstrated the chronic hypotensive effects of the AT1 antagonist losartan in normotensive, salt-replete rats. We hypothesized that the chronic effects of losartan are mediated in part by blockade of the central sympathoexcitatory actions of angiotensin II. To test this hypothesis, we have used a novel approach to effectively "clamp" the sympathetic nervous system at a fixed level through chronic administration of the ganglionic blocking agent hexamethonium (15 mg/kg/h) and the alpha agonist phenylephrine (2.26 mg/kg/d). Two of 3 groups of rats [CON and CLAMP(NNa)] were placed on (0.1%) NaCl diets, whereas the third [CLAMP(LNa)] was placed on a low (0.002%)-sodium diet. Continuous measurements of mean arterial pressure (MAP) were made via radiotelemetry. After 9 days of hexamethonium plus phenylephrine treatment in CLAMP(NNa) and CLAMP(LNa) rats, baseline MAP was not different in all 3 groups of rats: CON (104+/-4 mm Hg), CLAMP(NNa) (104+/-4 mm Hg), and CLAMP(LNa) (106+/-2 mm Hg). After 5 days of subsequent losartan treatment, a change in MAP of only -7+/-2 mm Hg was observed in CLAMP(NNa) rats compared with -22+/-2 mm Hg in CON and CLAMP(LNa) rats. These results do not support the hypothesis that the hypotensive actions of losartan are entirely dependent on a responsive sympathetic nervous system rats.